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Azabicyclooctane derivatives useful in the treatment of cardiac arrhythmias

a technology of azabicyclooctane and derivatives, which is applied in the direction of biocide, drug composition, cardiovascular disorder, etc., can solve problems such as (turning points

Inactive Publication Date: 2003-05-06
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The compounds of the invention have the advantage that they are effective against cardiac arrhythmias.

Problems solved by technology

One of the key disadvantages of hitherto known drugs which act by delaying repolarization (class m or otherwise) is that they all are known to exhibit a unique form of proarrhythmia known as torsades de pointes (turning of points), which may, on occasion be fatal.

Method used

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  • Azabicyclooctane derivatives useful in the treatment of cardiac arrhythmias
  • Azabicyclooctane derivatives useful in the treatment of cardiac arrhythmias
  • Azabicyclooctane derivatives useful in the treatment of cardiac arrhythmias

Examples

Experimental program
Comparison scheme
Effect test

preparation b

3-Benzyl-N-methyl-3-azabicyclo[3.2.1]octan-8-amine

A mixture of sodium cyanoborohydride (35.0 g, 0.557 mol) and zinc chloride (37.9 g, 0.278 mol) in methanol (500 mL) was added dropwise to a mechanically stirred mixture of 3-benzyl-3-azabicyclo[3.2.1]octan-8-one (Preparation A; 120 g, 0.557 mol) and methylamine hydrochloride (151 g, 2.23 mol) in methanol (1.0 L) at 25.degree. C. under nitrogen. After 2.5 h of stirring, 6 N NaOH (90 mL) was added dropwise. The mixture was filtered through a pad of Celite.RTM., washing with methanol (500 mL). The filtrate was concentrated in vacuo. Water (500 mL) was added, and the aqueous mixture was extracted with ethyl acetate (3.times.500 mL). The combined organic extracts were dried (Na.sub.2 SO.sub.4), and concentrated in vacuo. The residue was chromatographed, eluting with methanol dichloromethane (1:10), to afford 63.0 g (49%) of the sub-title compound as a solid.

.sup.1 H NMR (300 MHz, CCDl.sub.3): .delta. 7.40-7.10 (m, 5H), 3.88 (s, 2H), 3.60 ...

preparation d

tert-Butyl 3-Azabicyclo[3.2.1]oct-8-yl(methyl)carbamate

A solution of 1 M HCl in diethyl ether (730 mL, 730 mmol) was added dropwise to a solution tert-butyl 3-benzyl-3-azabicyclo[3.2.1]oct-8-yl(methyl)carbamate (Preparation C; 241 g, 0.730 mol) in diethyl ether (1.5 L). The resulting precipitate was collected via filtration through a sintered glass funnel and then dried in vacuo. The solid was dissolved in methanol (4.0 L), and 10% palladium on carbon (24 g) was added. The mixture was stirred under one atmosphere of hydrogen at 40.degree. C. overnight. The catalyst was filtered through a pad of Celite.RTM., washing with methanol (1.0 L). The filtrate was concentrated in vacuo, and chromatographed, eluting with dichloromethane:methanol:concentrated ammonium hydroxide (88:10:2) to afford 70 g (40%) of an oil. A solution of this oil (70 g, 296 mmol) in diethyl ether (1.0 L) was treated with 1 M HCl in diethyl ether (300 mL), added dropwise. The resulting precipitate was removed via fil...

example 1

tert-Butyl 8-{[3-(4-Cyanoanilino)propyl](methyl)amino}-3-azabicyclo[3.2. 1]octane-3-carboxylate

A mixture of 4-({3-[3-azabicyclo[3.2.1]oct-8-yl(methyl)amino]propyl}amino)benzonitrile (Preparation H; 170 mg, 0.569 mmol) and di-tert-butyldicarbonate (124 mg, 0.569 mmol) in dichloromethane (3.0 mL) was stirred for 2 h at 25.degree. C. under nitrogen. The mixture was concentrated in vacuo and the residue chromatographed on silica gel, eluting with ethyl acetate:dichloromethane (1:2), to yield 90 mg (40%) of the title compound as a colorless oil.

.sup.1 H NMR (300 MHz, CDCl.sub.3): .delta. 7.40 (d, J=8.2 Hz, 2H), 6.50 (d, J=8.2 Hz, 2H), 5.45 (s, 1H), 3.68-3.60 (m, 1H), 3.52-3.40 (m, 1H), 3.32-3.10 (m, 4H), 2.60 (s, 2H), 2.30 (s, 3H), 2.22-2.15 (m, 3H), 1.92-1.60 (m, 6H), 1.45 (s, 9H). .sup.13 C NMR (75 MHz, CDCl.sub.3): .delta. 156.4, 151.6, 133.6, 120.6, 112.0, 108.1, 79.4, 67.8, 54.2, 45.0, 44.0, 42.7, 39.8, 35.6, 28.4, 26.0, 25.4. CI-MS: (M+1)=399 m / z.

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Abstract

Compounds of formula I,wherein R1, R2, R3 and Ra Rh are as defined in the specification. The compounds are useful in the prophylaxis and in the treatment of arrhythmias, in particular a trial and ventricular arrhythmias.

Description

This application is a 371 of PCT / SE00 / 02064 filed Dec. 19, 2000, now WO 01 / 47893 Jul. 5, 2000.This invention relates to novel pharmaceutically useful compounds, in particular compounds which are useful in the treatment of cardiac arrhythmias.BACKGROUND AND PRIOR ARTCardiac arrhythmias may be defined as abnormalities in the rate, regularity, or site of origin of the cardiac impulse or as disturbances in conduction which causes an abnormal sequence of activation. Arrhythmias may be classified clinically by means of the presumed site of origin (i.e. as supraventricular, including atrial and atrioventricular, arrhythmias and ventricular arrhythmias) and / or by means of rate (i.e. bradyarrhythmias (slow) and tachyarrhythmias (fast)).In the treatment of cardiac arrhythmias, the negative outcome in clinical trials (see, for example, the outcome of the Cardiac Arrhythmia Suppression Trial (CAST) reported in New England Journal of Medicine, 321, 406 (1989)) with "traditional" antiarrhythmic d...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D221/24C07D221/00A61KA61K31/435C07D221/22A61K31/439A61K31/444A61K31/46A61K31/496A61K31/5377A61PA61P9/00A61P9/06C07DC07D401/12C07D405/12C07D413/12C07D417/12C40B40/04
CPCC07D221/24A61P9/00A61P9/06
Inventor BJORSNE, MAGNUSPONTEN, FRITIOFSTRANDLUND, GERTSVENSSON, PEDER
Owner ASTRAZENECA AB
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